Tumor necrosis factor alpha (TNF α) appears early in the inflammatory cascade following infection or injury. It is produced by monocytes, macrophages, and T lymphocytes. TNF α exists as both a soluble form, solTNF, which is believed to play an important role in inflammation, and a transmembrane form, tmTNF, which is involved in immune functions.
TNF α exerts its primary effects on monocytes, synovial macrophages, fibroblasts, chondrocytes, and endothelial cells, and stimulates proinflammatory cytokine and chemokine synthesis. It activates granulocytes, and increases MHC Class II expression. It promotes secretion of matrix metalloproteinases (MMPs), leading to cartilage matrix degradation, which indicates inflammation.
Because it initiates an inflammatory cascade, and has been found to be increased in close proximity to inflamed or injured tissue, TNF α inhibition is a target for pain and/or inflammation therapy and/or tissue destruction.
Proinflammatory TNF α is expressed on the plasma membrane, and then cleaved in the extracellular domain. Trimerization of TNF α is required for biological activity. TNF α acts through two receptors (TNFRs): Type I receptors (p60, p55, CD 120a) are expressed constitutively on most cell types and Type II receptors (p80, p75, CD 120b) are inducible. Popular TNF α inhibitors act primarily to inhibit binding of TNF α to its receptors.
There are currently two major classes of TNF antagonists or blockers: (i) monoclonal antibodies to TNF α, which prevent binding of TNF α to its two cell-associated signaling receptors (p55 and p75) and (ii) monomeric soluble forms of p55 or p75 TNF receptors (TNFR) dimerized by linking them to an immunoglobulin (Ig) Fc fragment. These immunoglobulins bind to TNF α with high affinity and prevent it from binding to its cell-associated receptor.
Several TNF antagonists have been developed for systemic administration and are approved for treating various diseases of the periphery such as rheumatoid arthritis and Crohn's disease. Currently available antagonists act on soluble, extracellular TNF or TNF receptors. While these agents are effective for the above-mentioned indications, this class of TNF antagonists is associated with the risk of serious side-effects, such as opportunistic infections, immuno-suppression and demyelinating diseases.
One particular TNF antagonist that is of interest is dominant-negative TNF α (DN-TNF). This type of TNF antagonist comprises engineered variants of human TNF that do not bind to TNF receptors, but exchange subunits with native homotrimers, forming inactive heterotrimers. DN-TNF has been shown to be a specific inhibitor of solTNF, but not tmTNF, eliminating the undesirable effects of solTNF inhibitors or antibodies (such as, for example, opportunistic infections, immuno-suppression and/or demyelinating diseases).
To date, however, DN-TNF has not been appreciated for treating pain and/or inflammation caused by proinflammatory cytokines, such as TNF α, associated with spinal disorders and/or osteoarthritis. Thus, there is a need to develop new methods of treating pain and/or inflammation caused by proinflammatory cytokines, such as TNF α, that are associated with spinal disorders and/or osteoarthritis.